Genetic Variant MARS2:p.Ser19Ser (chr2-197705462-T-C) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP7

The NM_138395.4(MARS2):c.57T>C(p.Ser19Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,460,550 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

MARS2
NM_138395.4 synonymous

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.375

Variant links:

Genes affected

MARS2 (HGNC:25133): (methionyl-tRNA synthetase 2, mitochondrial) This gene produces a mitochondrial methionyl-tRNA synthetase protein that is encoded by the nuclear genome and imported to the mitochondrion. This protein likely functions as a monomer and is predicted to localize to the mitochondrial matrix. Mutations in this gene are associated with the autosomal recessive neurodegenerative disease spastic ataxia-3 (SPAX3). [provided by RefSeq, Apr 2014]

MARS2 links:

ENSG00000222017 (HGNC:):

ENSG00000222017 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP7

Synonymous conserved (PhyloP=0.375 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MARS2	NM_138395.4 link	c.57T>C	p.Ser19Ser	synonymous_variant	Exon 1 of 1	ENST00000282276.8	NP_612404.1	Q96GW9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MARS2	ENST00000282276.8 link	c.57T>C	p.Ser19Ser	synonymous_variant	Exon 1 of 1	6	NM_138395.4	ENSP00000282276.6		Q96GW9
ENSG00000222017	ENST00000409845.1 link	n.166+6598T>C		intron_variant	Intron 2 of 3	1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000161

AC:

AN:

248076

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135022

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000360

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000548

AC:

AN:

1460550

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726592

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000719

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Mar 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects codon 19 of the MARS2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MARS2 protein. This variant is present in population databases (no rsID available, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with MARS2-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

9.9

DANN

Benign

0.71

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over